Abstract
Apoptosis of islet β cells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4)/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER) stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces islet β cell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro. We demonstrated that the high glucose/palmitate intervention induced the expression and secretion of Par-4. It also causes increased expression and activation of NF-κB, which induced NIT-1 cell apoptosis and dysfunction. Overexpression of Par-4 potentiates these effects, whereas downregulation of Par-4 attenuates them. Inhibition of NF-κB inhibited the Par-4-induced apoptosis. Furthermore, these effects occurred through the ER stress cell membrane and mitochondrial pathway of apoptosis. Our findings reveal a novel role for Par-4/NF-κB in islet β cell apoptosis and type 2 diabetes.
Highlights
The basic pathogenic process of type 2 diabetes consists of islet β cell loss and dysfunction
Apoptosis is the main cause of islet β cell loss and dysfunction [1]; the overload of glucose and fatty acid induces the gathering of reactive oxide species (ROS), oxide-stress, and the increasing of endoplasmic reticulum (ER) stress and mitochondrial dysfunction attenuates the islet β cell apoptosis and dysfunction and contributes to the development of diabetes, the so called glucolipotoxicity [2,3,4]
We analyzed prostate apoptosis response-4 (Par-4) expression by western blot (WB) in NIT-1 cells and found that it was highly expressed after the high glucose/palmitate intervention compared with the control group (Figure 1(a))
Summary
The basic pathogenic process of type 2 diabetes consists of islet β cell loss and dysfunction. Severe metabolic disorders induce ER stress and mitochondrial dysfunction and initiate the apoptosis pathway, including the cell membrane and mitochondrial pathways. This may be the common mechanism for islet β cell apoptosis, which is induced by glucolipotoxicity [5,6,7]. It is unclear what promotes ER stress and mitochondrial dysfunction in type 2 diabetes
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